Agonist binding to GPCRs causes rapid phosphorylation of the activated receptors by GPCR kinases. This process promotes the recruitment of members of the arrestin protein family (beta-arrestin-1 and -2) to the activated receptors, disrupting receptor/G protein coupling and promoting GPCR internalization by targeting the receptors to clathrin-coated pits. However, during the past 10-15 years, many studies have demonstrated that beta-arrestins can also act as signaling molecules in their own right. This observation is not only of theoretical interest but also of potential clinical relevance. During the past few years, DREADDs (designer receptors exclusively activated by designer drug) have emerged as powerful novel chemogenetic tools to study the physiological relevance of signaling pathways activated by different functional classes of GPCRs. Structurally, DREADDs represent mutant muscarinic receptors that can be activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert agent, with high potency and efficacy. Importantly, these new designer receptors cannot be activated by acetylcholine, the endogenous muscarinic receptor agonist. Consistent with the GPCR-like properties of DREADDs, we recently demonstrated that an M3 muscarinic receptor (M3R)-based DREADD does not only activate G proteins of the Gq family but can also interact with beta-arrestin-1 and -2 and trigger beta-arrestin-dependent downstream signaling. Taken together, these findings support the concept that the physiological outcome of activating a specific GPCR (or DREADD) in a particular tissue or cell type represents an integrated response caused by the activation of both G protein- and beta-arrestin-dependent signaling pathways. To gain insight into the physiological relevance of these two distinct GPCR signaling branches, it is important to assess the relative contribution of G protein- and beta-arrestin-dependent signaling to a particular tissue response. To shed light on this issue, we generated an M3R-based beta-arrestin-biased DREADD as well as an M3R-based Gq/11-biased DREADD that lacks the ability to interact with beta-arrestins (Wess J. Trends Endocrinol Metab 27, 600-3, 2016). These functionally biased DREADDs represent powerful new tools to study the physiological relevance of Gq/11- vs. beta-arrestin-dependent signaling cascades in distinct tissues and cell types. Importantly, such information could be exploited for developing novel classes of clinically useful drugs, including G protein- or beta-arrestin-biased agonists.